TNAP: a new player in cardiac fibrosis? Focus on "Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts".

Abstract

FIBROSIS OF THE HEART, caused by overproduction of extracellular matrix (ECM) proteins by fibroblasts, has diverse negative functional consequences. For example, fibrosis increases the passive stiffness of the myocardium, resulting in diastolic dysfunction (9), and disrupts electrical conduction in the heart, causing arrhythmias (3). Additionally, the quantity of fibrosis in the heart is predictive of adverse cardiac outcomes (4). Despite the well-accepted role of fibrosis in the pathogenesis of numerous cardiac and noncardiac diseases, there is only one FDA-approved antifibrotic therapy, pirfenidone, for the treatment of idiopathic pulmonary fibrosis. While encouraging, unfortunately the molecular target(s) of pirfenidone are unknown, and the efficacy of the drug is limited, with no impact on quality of life, symptoms, or mortality (6). This highlights the need to more extensively define the molecular mechanisms that control fibrosis, with the goal of revealing novel therapeutic targets that can impact hard outcomes. Lee and colleagues provide evidence that tissue-nonspecific alkaline phosphatase (TNAP) serves a novel role in the activation of cardiac fibroblasts, and thus may contribute to cardiac fibrosis (8). This new finding stemmed from the group’s work on secreted frizzled-related protein 2 (sFRP2), which physically associates with Wnt ligands and prevents them from transducing intracellular signals via frizzled transmembrane receptors. Wnt-dependent and -independent roles for sFRP2 in cardiac fibrosis have previously been suggested. Through a Wnt-independent mechanism, sFRP2 was shown to enhance tolloid-like metalloproteinases to cleave procollagen into collagen and promote fibrosis of the heart, and mice lacking sFRP2 were found to be protected from adverse remodeling post-myocardial infarction (MI) (7). Consistent with a profibrotic role for sFRP2, the Lee group previously demonstrated that a blocking antibody against sFRP2 repressed cardiac fibrosis and improved systolic function in the TO2 -sarcoglycan-null cardiomyopathic hamster model (10). However, blockade of sFRP2 was associated with reduced Wnt signaling in this model, suggesting that sFRP2 also stimulates cardiac fibrosis through a Wnt-dependent mechanism. Adding further complexity was the demonstration that intracardiac injection of recombinant sFRP2 paradoxically reduces cardiac fibrosis in a rat MI model (5). It has been proposed that these contradictory findings (stimulation and inhibition of fibrosis by sFRP2) are related to the ability of sFRP2 to enhance or inhibit Wnt signaling depending on dosage, with low and high sFRP2 concentrations stimulating and inhibiting Wnt, respectively (10). In the current study, the Lee group noted that TO2 hamster hearts have concomitant fibrosis and calcification; fibrotic plaques can become calcified through a process known as fibrocalcification. Based on this finding, the authors began assessing the possible connection to TNAP, an ectoenzyme that promotes calcification by hydrolyzing inorganic pyrophosphate (PPi), a potent mineralization inhibitor, into inorganic phosphate (Pi) (Fig. 1). In addition to its function in normal bone development, TNAP has been implicated in the pathogenesis of vascular calcification. The authors found that TNAP expression and activity were elevated in TO2 hearts and in pigs with ischemic cardiomyopathy due to stenosis of the left anterior descending and left circumflex coronary arteries. TNAP activity was reduced in hearts of TO2 hamsters treated with sFRP2 blocking antibody, while treatment of cultured mouse cardiac fibroblasts with recombinant sFRP2 led to increased TNAP expression and activity. Together, these findings suggest that sFRP2 enhances cardiac fibrosis, and possibly fibrocalcification of the heart, by stimulating TNAP activity. Given the intriguing findings of the Lee group, and the recent demonstration that TNAP promotes cardiomyocyte hypertrophy (2), efforts to further understand the roles of TNAP in pathological cardiac remodeling are justified, and the next steps should be relatively straightforward. First, the generalizability of the current findings should be addressed by quantifying TNAP activity in additional preclinical models of heart failure (e.g., pressure overload and chronic angiotensin signaling) and, more crucially, TNAP activity should be measured in explanted hearts from humans with heart failure. The importance of this additional work is underscored by the fact that overt interstitial calcification within the myocardium, as shown in TO2 hamsters, is not a prominent feature of chronic heart failure in humans. Therefore, it will be critical to rule out the possibility that TNAP-driven cardiac fibrosis is limited to the cardiomyopathic hamster model; the findings with pig hearts are encouraging but need to be expanded. Second, the impact of fibroblast-specific genetic knockdown/knockout of TNAP on ECM gene expression and fibrosis should be determined.